Experimental Systems for Measuring HIV Latency and Reactivation

Fujinaga, Koh; Cary, Daniele C.

doi:10.3390/v12111279

Cited by 19 publications

(19 citation statements)

References 196 publications

(240 reference statements)

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“…From our and other studies, we also know that resting and memory T cells lack P-TEFb (Garriga et al, 1998;Ghose et al, 2001). Thus, proviral latency is maintained in these cells (Fujinaga & Cary, 2020). This situation most likely pertains to other DNA viruses, such as HSV and HTLV1/2 in yet other resting or terminally differentiated cells (Kulkarni & Bangham, 2018;Nicoll, Proenca, & Efstathiou, 2012).…”

Section: Discussionmentioning

confidence: 60%

Reversible phosphorylation of cyclin T1 promotes assembly and stability of P-TEFb

Huang

Nguyen

Echeverria

et al. 2021

eLife

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The positive transcription elongation factor b (P-TEFb) is a critical coactivator for transcription of most cellular and viral genes, including those of HIV. While P-TEFb is regulated by 7SK snRNA in proliferating cells, P-TEFb is absent due to diminished levels of CycT1 in quiescent and terminally differentiated cells, which has remained unexplored. In these cells, we found that CycT1 not bound to CDK9 is rapidly degraded. Moreover, productive CycT1:CDK9 interactions are increased by PKC-mediated phosphorylation of CycT1 in human cells. Conversely, dephosphorylation of CycT1 by PP1 reverses this process. Thus, PKC inhibitors or removal of PKC by chronic activation results in P-TEFb disassembly and CycT1 degradation. This finding not only recapitulates P-TEFb depletion in resting CD4+ T cells but also in anergic T cells. Importantly, our studies reveal mechanisms of P-TEFb inactivation underlying T cell quiescence, anergy, and exhaustion as well as proviral latency and terminally differentiated cells.

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Section: Discussionmentioning

confidence: 60%

Reversible phosphorylation of cyclin T1 promotes assembly and stability of P-TEFb

Huang

Nguyen

Echeverria

et al. 2021

eLife

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“…The use of HIV latently infected cell lines as models for screening compounds to suppress or inhibit HIV production has been widely used [ 37 ]. The HIV gene expression has been in low to undetectable levels but increased once stimulated.…”

Section: Resultsmentioning

confidence: 99%

Voacanga globosa Spirobisindole Alkaloids Exert Antiviral Activity in HIV Latently Infected Cell Lines by Targeting the NF-κB Cascade: In Vitro and In Silico Investigations

et al. 2022

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Since the efficiency in the transcription of the HIV genome contributes to the success of viral replication and infectivity, we investigated the downregulating effects of the spirobisindole alkaloids globospiramine (1), deoxyvobtusine (2), and vobtusine lactone (3) from the endemic Philippine medicinal plant, Voacanga globosa, during HIV gene transcription. Alkaloids 1–3 were explored for their inhibitory activity on TNF-α-induced viral replication in two latently HIV-infected cell lines, OM10.1 and J-Lat. The induction of HIV replication from OM10.1 and J-Lat cells elicited by TNF-α was blocked by globospiramine (1) within noncytotoxic concentrations. Furthermore, globospiramine (1) was found to target the NF-ĸB activation cascade in a dose-dependent manner when the transcriptional step at which inhibitory activity is exerted was examined in TNF-α-induced 293 human cells using transient reporter (luciferase) gene expression systems (HIV LTR-luc, ĸB-luc, and mutant ĸB-luc). Interrogation through molecular docking against the NF-ĸB p50/p65 heterodimer and target sites of the subunits comprising the IKK complex revealed high binding affinities of globospiramine (1) against the S281 pocket of the p65 subunit (BE = −9.2 kcal/mol) and the IKK⍺ activation loop (BE = −9.1 kcal/mol). These findings suggest globospiramine (1) as a molecular inspiration to discover new alkaloid-based anti-HIV derivatives.

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“…From our and other studies, we also know that resting and memory T cells lack P-TEFb (Garriga et al, 1998;Ghose et al, 2001). Thus, proviral latency is maintained in these cells (Fujinaga & Cary, 2020). This situation most likely pertains to other DNA viruses, such as herpes simplex virus and HTLV1/2 in yet other resting or terminally differentiated cells (Kulkarni & Bangham, 2018;Nicoll, Proenca, & Efstathiou, 2012).…”

Section: Discussionmentioning

confidence: 58%

Assembly and levels of P-TEFb depend on reversible phosphorylation of cyclin T1

Huang

Nguyen

Echeverria

et al. 2021

Preprint

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The positive transcription elongation factor b (P-TEFb) is a critical co-activator for transcription of most cellular and viral genes, including those of HIV. While P-TEFb is regulated by 7SK snRNA in proliferating cells, it is absent in quiescent and terminally differentiated cells, which has remained unexplored. In these cells, we found that CycT1 not bound to CDK9 is rapidly degraded. Moreover, productive CycT1:CDK9 interactions require phosphorylation of two threonine residues (Thr143 and Thr149) in CycT1 by PKC. Conversely, PP1 dephosphorylates these sites. Thus, PKC inhibitors or removal of PKC by chronic activation results in P-TEFb disassembly and CycT1 degradation. This finding not only recapitulates P-TEFb depletion in resting CD4+ T cells but also in anergic T cells. Importantly, our studies reveal mechanisms of P-TEFb inactivation underlying T cell quiescence, anergy, and exhaustion as well as proviral latency and terminal differentiation of cells.

show abstract

Experimental Systems for Measuring HIV Latency and Reactivation

Cited by 19 publications

References 196 publications

Reversible phosphorylation of cyclin T1 promotes assembly and stability of P-TEFb

Reversible phosphorylation of cyclin T1 promotes assembly and stability of P-TEFb

Voacanga globosa Spirobisindole Alkaloids Exert Antiviral Activity in HIV Latently Infected Cell Lines by Targeting the NF-κB Cascade: In Vitro and In Silico Investigations

Assembly and levels of P-TEFb depend on reversible phosphorylation of cyclin T1

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